Clinical Status and Optimal Use of New Therapeutic Agents

Over the past few years, several promising new therapeutic agents have been approved by the FDA for the treatment of cancer patients. In addition, other commercially available drugs have been licensed for supplemental indications. The more rapid approval process for oncology drugs has resulted in the widespread use of agents, often before the clinician has sufficient information about their appropriate indications. In this issue of ONCOLOGY, we begin a new series of articles focusing on newly approved agents. The authors of these articles, many of whom were instrumental in the development of the new drugs, have been asked to summarize the clinical experience with and recommended uses for these compounds.

Some of the drugs featured in this issue were discovered during the decades of research devoted to identifying analogs of currently available drugs. These efforts were fueled by the hope that the analogs would exhibit either increased or comparable efficacy and reduced toxicity compared with the parent compound. Gemcitabine (Gemzar), discussed in this issue by Drs. Michael Michael and Malcolm Moore, is one of several nucleoside analogs now in clinical use, but, unlike other commonly used nucleosides (eg, cytarabine, fludarabine [Fludara], and cladribine [Leustatin]), gemcitabine exhibited activity against a broad range of solid tumors in preclinical models. Gemcitabine was recently approved by the FDA for the treatment of pancreatic cancer, not on the basis of its rather limited activity, but primarily because it led to an improvement in disease-related symptoms in approximately one-quarter of patients.

More recently, a considerable effort in drug development has focused on discovering compounds with unique mechanisms of action. The topoisomerase inhibitors represent one such novel class of drugs. Two of these agents, topotecan (Hycamtin) and irinotecan (CPT-11 [Camptosar]), are commercially available. A third, 9-amino-camptothecin, is still undergoing clinical investigation. Topotecan, as described in the paper by Drs. Chris Takimoto and Susan Arbuck, was approved by the FDA 7 years after entering clinical trials, based on the results of a phase III trial in woman with relapsed ovarian cancer. The overall response rate with topotecan in this trial was 21%, which was considered to be at least equivalent to the 15% response rate with paclitaxel (Taxol).

Another newly approved therapeutic agent profiled in this issue is anastrozole (Arimidex). As discussed by Drs. Paul Goss and Lesley Tye, anastrozole is a third-generation inhibitor of estrogen synthetase that is more selective than its predecessor, aminoglutethimide. Phase III trials in postmenopausal women with advanced breast cancer showed an objective tumor response rate of 10.3% with anastrozole, as compared with 7.9% with megestrol acetate, albeit with no difference in time to progression (21 weeks) or overall survival.

Other agents have been approved for use in cancer patients, not because they are therapeutic, but rather, because they improve quality of life or provide some measure of supportive care. As an example, in the fourth paper in this special issue, Dr. Ronald Blum presents data indicating that dexrazoxane (Zinecard) therapy results in a significant reduction in the frequency of anthracycline-induced cardiotoxicity.

There are many unresolved issues surrounding the development of new antineoplastic drugs. When they are administered to patients with relapsed or refractory tumors, it is with palliative intent. Response rates and duration of response will likely be greater when patients receive these drugs as part of their initial treatment program. However, it is obvious that, even as front-line treatment, none of these drugs will be curative when administered as single agents. Therefore, one of the most important unanswered questions is how to best develop rational combinations with other active drugs that will result in increased efficacy compared with the activity of each single component. Too often, agents are combined simply because each exhibits some activity against a particular tumor type. The seemingly never-ending array of drug combinations and permutations generated by the empiric approach has rarely been successful in significantly enhancing efficacy, and is not an efficient use of time and resources.

So, how can we better direct our efforts to make significant advances, rather than small incremental steps, in anticancer therapy? The first step should be aimed at gaining a better characterization of the genetic, molecular, and immunologic lesions resulting in malignancy and tumor progression. As these therapeutic targets are identified, specific therapeutic strategies can be directed at them.

Second, and equally important, should be a commitment to increase accrual of patients to important clinical trials. Only through the close interaction between laboratory scientists and clinical researchers, and the expedient testing of new therapies, will we be able to achieve the goal of cure.